This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
U.S. Pat. No. 4,022,900 (Marion) discloses benzamido-tetrahydroisoquinolines having anti-hypertensive and vasodilator properties, including the compound 2,4,5-trimethoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide.
The compound N-[2-(1-methyl-pyrrolidin-2-yl)-phenyl]benzamide is disclosed in JACS 1976, 98, p6321.
It has now been surprisingly found that benzamide compounds of formula (I) below possess anti-convulsant activity and are therefore believed to be useful in the treatment and/or prevention of anxiety, mania, depression disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, panic disorders and/or aggression.
Accordingly, the present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof. 
where
G is a methylene or ethylene linkage;
R1 is hydrogen, C1-6 alkylOxe2x80x94;
R2 is hydrogen, halogen, CN, N3, trifluoromethyldiazirinyl, CF3, CF3Oxe2x80x94, CF3Sxe2x80x94, CF3COxe2x80x94, C1-6alkyl, C3-6cycloalkyl,C3-6cycloalkyl-C1-4alkyl-, C1-6alkylOxe2x80x94, C1-6alkylCOxe2x80x94, C3-6cycloalkylCOxe2x80x94, C3-6cycloalkyl-C1-4alkylCOxe2x80x94, phenyl,phenoxy, benzyloxy, benzoyl and substituted benzoyl, phenyl-C1-4alkyl-, C1-6alkylSO2xe2x80x94, (C1-4alkyl)2NSO2xe2x80x94 or (C1-4alkyl)NHSO2xe2x80x94;
R3 is hydrogen, halogen, CN, N3, trifluoromethyldiazirinyl, C1-6 alkylOxe2x80x94, C1-6 alkylSxe2x80x94, C1-6 alkyl, C3-6cycloalkyl,C3-6cycloalkyl-C1-4alkyl-, C1-6alkenyl, C1-6alkynyl, CF3COxe2x80x94, C1-6alkylCOxe2x80x94, C3-6cycloalkylCOxe2x80x94, C3-6cycloalkyl-C1-4alkylCOxe2x80x94, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, or xe2x80x94NR5R6 where R5 is hydrogen or C1-4 alkyl, and
R6 is hydrogen, C1-4alkyl, xe2x80x94CHO, xe2x80x94CO2C1-4alkyl or xe2x80x94COC1-4alkyl;
R4 is hydrogen, C1-6 alkyl, C1-6 alkenyl, or C1-6 alkynyl.
The compounds of this invention are typically (2-pyrrolidin/2-piperidin-yl-phenyl)-benzamides.
In the formula (I), groups are typically based on straight chain alkyl groups, but in general alkyl groups may be straight chain or branched.
Suitable C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Further, it should be appreciated that whenever the term phenyl is mentioned above, the phenyl moiety is optionally substitued for example it is independently substituted one or more times by a substituent selected from the list comprising halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylcarbonyl.
Suitable halo substituents include fluoro, chloro, iodo and bromo.
A suitable group of compounds of formula (I) have
R1 as methoxy, ethoxy or n-propoxy
R2 as hydrogen, methoxy, bromo, chloro, iodo, acetyl, benzoyl, trifluoromethyl, trifluoroacetyl.
R3 as hydrogen, methyl, ethyl, n-butyl, t-butyl, phenyl, methoxy, ethoxy, isopropoxy, n-butoxy, benzyloxy, amino, acetylamino, benzoyl, chloro or azido
R4 as hydrogen, methyl, ethyl or propyl.
Examples of compounds of formula (I) are:
2-[3-(4-tert-butyl-2-methoxy-benzoylamino)-phenyl]-pyrrolidine.
2-[3-(4-tert-butyl-2-methoxy-benzoylamino)-phenyl]-piperidine.
When synthesised, these compounds are often in salt form, typically the hydrochloride or trifluoroacetate, and such salts also form part of this invention. Such salts may be used in preparing pharmaceutically acceptable salts. The compounds and their salts may be obtained as solvates, such as hydrates, and these also form part of this invention. It should be appreciated that the present compounds possess a chiral centre, therefore the present invention extends to each enantiomer separately and to all mixtures of enantiomers including racemates.
The above compounds and pharmaceutically acceptable salts thereof, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, form a preferred aspect of the present invention.
The administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual or transdermal administration.
An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 1 to 5000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 5000 mg, for example 1 to 1500 mg, that is in the range of approximately 0.01 to 70 mg/kg/day, for example 0.1 to 20 mg/kg/day.
It is greatly preferred that the compound of formula (I) is administered in the form of a unit-dose composition, such as a unit dose oral, including sub-lingual, rectal, topical or parenteral (especially intravenous) composition.
Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.
Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
These solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
For parenteral administration, fluid unit dose forms are prepared containing the compound and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
The present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of anxiety, mania, depression disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigerninal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, panic disorders and/or aggression, which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
The present invention also provides a method of treatment and/or prevention of anxiety, mania, depression disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, panic disorders and/or aggression comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
In a further aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prevention of anxiety, mania, depression disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, panic disorders and/or aggression.
In a further aspect the present invention provides a pharmaceutical composition containing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
In a further aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as a therapeutic agent, in particular for the treatment and/or prevention of anxiety, mania, depression disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimrer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, panic disorders and/or aggression.
Another aspect of the invention provides a process for the preparation of compounds of formula (I), which comprises reacting a compound of formula (II) 
where G is as defined for formula (I) and R4A is R4 as defined for formula (I) or a group convertible to R4 or a protecting group
xe2x80x83with a compound of formula (III) 
where Y is Cl or other halogen or OH, and R1A, R2A, and R3A are respectively R1, R2, and R3 as defined for formula (I) or groups convertible to R1, R2, and R3,
and where required converting a R1A, R2A, R3A or R4A group to a R1, R2, R3 or R4 group, converting one R1, R2, R3 or R4 group to another R1, R2, R3 or R4 group, converting a hydrochloride salt product to the free base or another pharmaceutically acceptable salt, or converting a free base product to a pharmaceutically acceptable salt.
Reaction of a compound of formula (III) which is a benzoyl chloride derivative Yxe2x95x90Cl) will lead directly to the hydrochloride salt. Suitable solvents include dichloromethane and ethyl acetate. A base such as triethylamine may be used. When the compound of formula (III) is a benzoic acid derivative (Yxe2x95x90OH), conventional conditions for condensation of aromatic acids with amines may be used, for example reacting the components in a mixture of 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide, hydroxybenzotriazole in a solvent such as dimethylformamide.
Conversions of an R1A, R2A, R3A or R4A group to a R1, R2, R3 or R4 group typically arise when a protecting group is needed during the above coupling reaction or during the preparation of the reactants by the procedures described below. Interconversion of one R1, R2, R3 or R4 group to another typically arises when one compound of formula (I) is used as the immediate precursor of another compound of formula (I) or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence.
Compounds of formula (II) where G is methylene may be prepared from a compound of formula (IV) 
by hydrogenation of the pyrrole ring, for example using hydrogen/platinum in a suitable solvent such as methanol at ambient temperature and pressure.
Compounds of formula (IV) may be prepared by reaction of a halo-aniline with a boronic acid derivative of a R4A-substituted pyrrole (e.g. t-butyloxycarbonyl protected). Using Na2CO3/DME(dimethoxyethane)/H2O cat Pd(PPh3)4 as a palladium (o) catalyst. Or in the case of piperidine analogs 2-halopyridine (e.g. 2-bromopyridine) is coupled with a suitable aminophenyl boromic acid under similar conditions. Acylation (EDC, HOBT, DMF) with a compound of formula (III) followed by quaternisation with R4X, where X is a leaving group such as halgen, for example iodine. Examples of R4X specifically include methyl iodide, which may be reacted in an inert organic solvent such as acetone followed by hydrogeneration using conventional conditions such as (Pt Oc, H2, methanol) to give a compound of formula (I).
Compounds of formula (III) can be prepared by further substitution of commercially available benzoic acid derivatives using conventional procedures. Suitable starting materials are 2,4-dimethoxy benzoic acid, 2-methoxy 4-tert-butyl benzoic acid and 2-methoxy 4-chloro benzoic acid.
It should be appreciated that amines of formula (II) are suitably resolved using conventional technique before reacting with a compound of formula (III). Alternatively, compounds of formula (I) which are enantiomeric mixtures may be resolved using conventional techniques.
The preparation of compounds of this invention is further illustrated by the following Preparations and Examples. The utility of compounds of this invention is shown by the Pharmacological Data that follow the Examples.
Preparation 1
A mixture of 3-bromoaniline (0.48 g), N-tert-butyloxycarbonyl-2-pyrrole-boronic acid (0.6 g), sodium carbonate (0.91 g), tetrakis-(triphenylphosphine) palladium (1.3 g) in DME (30 mL) and water (5 mL) was heated under reflux under argon for 16 h. The reaction mixture was allowed to cool to room temperature and poured into water. It was then extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo. Repeated suction silica gel chromatography eluting with ethyl acetate in hexane (from 10% to 50%, 10% increments) gave desired product as an amber solid (0.3 g).
Mass Spectroscopy (API+) gave molecular ion peak at 259 as M+1.
Preparation 2
A solution of 2-(3-aminophenyl)-1-tert-butyloxycarbonyl)-pyrrole (0.3 g) in the presence of 5% platinum on carbon (0.03 g) in methanol (30 rnL) was allowed to stir under an atmosphere of hydrogen for 18 h. The reaction mixture was filtered through a pad of Kieselguhr and the filtrate evaporated in vacuo to dryness. Suction silica gel chromatography of the residue eluting with ethyl acetate followed by methanol/ethyl acetate (5% to 10%) gave the title compound as an amber oil (0.05 g).
1H (250 MHz, CDCl3): 1.22 and 1.45 (9H, 2 br. s); 1.85 and 2.25 (4H, 2 br. m); 3.6 (4H, br. s); 4.68 and 4.87 (1H, 2 br. s); 6.5 (3H, m); 7.07 (1H, t).
Preparation 3
To a solution of 4-tert-butyl-2-methoxy-benzoic acid (0.05 g) in DMF (1.5 mL) at room temperature, was added in order, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.046 g), 1-hydroxy-benzotriazole (0.033 g) and 15 min. later, (xc2x1)-2-(3-aminophenyl)-1-(tert-butyloxycarbonyl)-pyrrolidine (0.05 g). The reaction mixture was allowed to stir for 17 h and then poured into water. The aqueous mixture was extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo to afford an amber oil. Suction silica gel chromatography eluting with ethyl acetate in hexane (from 30% to 100%, in 10% increments) gave desired product as an amber solid (0.03 g).
1H (400 MHz, CDCl3): 1.22 and 1.46 (9H, 2 br. s); 1.36 (9H, s); 1.80-2.00 and 2.34 (4H, m); 3.60 (2H, 2 br. s); 4.07 (3H, s); 4.79 and 4.95 (1H, 2 br. s); 6.92 (1H, d); 7.02 (1H, s); 7.15 (1H, d); 7.27 (1H, t); 7.47 (1H, br. s); 7.55 (1H, br. s); 8.20 (1H, d); 9.78 (1H, br. s)